A genome-wide search for human type I diabetes susceptibility genes using microsatellite markers confirmed that MHC linked genes are the dominant inherited risk factor. Human MHC class II genes encoding the chains of HLA-DQ8 (DQB1*0302) and DQ2 (DQB1*0201) are high risk alleles. Structural definition of the peptide binding sites and identification of the self- peptides presented by these MHC molecules will be critical for understanding the pathogenetic mechanisms that lead to the loss of T cell tolerance in IDDM. The major goals of this program project are: 1. to determine the crystal structure of HLA-DQ8 and DQ2 complexed with peptides from immunodominant islet cell antigens, 2. to develop non-peptidic blockers that are selective for the peptide binding sites of HLA-DQ8 and DQ2, 3. to generate HLA-DQ8 transgenic NOD mice as an animal model for IDDM, 4. to define HLA- DQ8 restricted T cell epitopes of islet cell autoantigens and 5. to express bivalent DQ8/peptide complexes as T cell receptor specific probes for the detection and depletion of diabetogenic T cells. The program is focused on the common goal of defining the molecular mechanisms of MHC-linked susceptibility to IDDM. The program project combines investigators with unique areas of expertise in structural biology, chemistry, mouse genetics and T cell immunology who will integrate recent advances in their respective fields to accomplish this goal. A biweekly data club and seminar series will further strengthen this collaborative and interactive research program.